Project 3 - The Estrogens, Cardiometabolic Health, and Female Cognitive Aging Program Project at Tulane University

Project 3:

Impact of estradiol on vascular health and subsequent implications for cognitive aging

The overall hypothesis of Project 3 is that cardiovascular disease alters estrogen receptor profile, disrupting the integration of estrogen’s molecular signaling pathways and attenuating estrogen’s cardiovascular effects and downstream protection from Alzheimer’s disease and vascular dementia.

Schematic showing the effects of estrogens on healthy versus unhealthy arteries. The healthy artery shows larger images of GPER and ERa than the unhealthy artery implying an increased activation of the two compounds in the healthy artery. The middle of the healthy artery (left) shows text indicating increased vasodilation, decreased oxidative stress, decreased blood pressure, decreases stiffness and decreased remodeling. The hypertensive (unhealthy) artery on the right shows text indicating decreased vasodilation, increased oxidative stress, increased blood pressure, increased stiffness and increased remodeling.

Hypothesized model by which effects of estrogens in the vasculature diverge in healthy versus unhealthy arteries. If arteries are healthy when treatment with estrogens is initiated, estrogens activate both the G protein-coupled receptor (GPER) and estrogen receptor alpha (ERα) to induce vasodilation and decrease oxidative stress, blood pressure, arterial stiffness, and vascular remodeling. These protective effects in the vasculature positively impact the brain and cognition. If arteries are unhealthy due to hypertension or other cardiovascular diseases when treatment with estrogens is initiated, GPER and ERα expression and/or signaling are downregulated so the vascular effects as well as downstream impact on the brain are reduced. Created with BioRender.com

Left Hand panel of a graph showing two lines. The top line, made up of white squares shows a relatively steady increase. The bottom line, made up of pink circles, shows a slight decrease, then increase. Right Hand panel of a bar graph made up of two sets of two vertical bars with white representing OVX+Veh and Pink representing OVX+E. The first set representing the surface shows a white bar with a value just above two and a pink bar just below 3. The second set representing the hippocampus shows a white bar at around 3 and a pink bar at around 1.5.

Left: Using Co-I Dr. Daniel’s rat model of postmenopausal cognitive dysfunction, we found increased blood pressure 8 weeks post-ovariectomy (OVX; *P<0.05 vs. week 1) that was prevented by estrogen (E). Right: New data show that E also reduces vascular remodeling in hippocampal but not surface blood vessels (*P<0.05).

Aim 1:

Cardiovascular disease affects vascular response to hormone therapy

Determine the impact of cardiovascular disease on the vascular response to hormone therapy.

Assess vascular/cognitive effects of estrogen in the presence of cardiovascular disease
Determine if estrogen’s effects are dependent on disease initiation pre- or post-menopause
Assess how delayed estrogen treatment affects vascular and cognitive function

Aim 2:

Cardiovascular disease alters estrogen receptor expression

Determine whether cardiovascular disease disrupts estrogen receptor profile to impact the response to hormone therapy.

Evaluate the impact of cardiovascular
disease on estrogen receptor expression and signaling
Determine the impact of estrogen receptor deletion on vascular/cognitive dysfunction

Logarithmic graph showing three lines: Ang II-treated in blue, Middle aged female in green, and young female in red. All three lines show a logarithmic decrease, red being most dramatic and blue being significantly less dramatic of a decrease.

Data from our laboratory shows that either Ang II hypertension or aging significantly decrease the vasodilatory response to estradiol (E2; *P<0.05).

Blue and green fluorescent image of aortic rings.

Immunofluorescence of aortic rings allows detection of proteins of interest as well as their localization within the intimal, medial, or adventitial layers.

Aim 3:

Arterial stiffness diminishes the protective effects of estrogen on the female brain

Assess the impact of hypertension versus arterial stiffness on female cognition, dendritic plasticity, and neurovascular coupling.

Evaluate effects of hypertension and arterial stiffening on estrogen’s protective effects on dendritic plasticity and neurovascular coupling
Identify antihypertensive treatments that restore the protective effects of estrogen on the brain

Project 3: